Aswan Heart Centre, Magdi Yacoub Heart Foundation, Kasr El Haggar Street, Aswan 81512, Egypt.
National Heart and Lung Institute, Imperial College London, London, Guy Scadding Building, Dovehouse St, London SW3 6LY, UK.
Eur Heart J. 2023 Dec 21;44(48):5146-5158. doi: 10.1093/eurheartj/ehad372.
Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls.
Prospective Egyptian patients (n = 514) and controls (n = 400) underwent clinical phenotyping and genetic testing. Rare variants in 13 validated HCM genes were classified according to standard clinical guidelines and compared with a prospective HCM cohort of majority European ancestry (n = 684). A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10-7), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (five-fold greater than European patients), highlighting the importance of recessive inheritance in consanguineous populations. Finally, rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10-5) due to the underrepresentation of Middle Eastern populations in current reference resources. This proportion increased to 53.3% after incorporating methods that leverage new ancestry-matched controls presented here.
Studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.
肥厚型心肌病（HCM）的表型具有异质性，部分原因是导致疾病的遗传变异多样性。准确解释这些变异对诊断和实施精准医学构成了重大挑战，尤其是在研究较少的人群中。本研究旨在利用具有高近亲结婚率的北非队列，通过与具有匹配祖源的病例和对照，来定义 HCM 的遗传结构。
前瞻性埃及患者（n = 514）和对照（n = 400）接受了临床表型和基因检测。根据标准临床指南对 13 个验证过的 HCM 基因中的罕见变异进行分类，并与具有多数欧洲祖源的前瞻性 HCM 队列（n = 684）进行比较。埃及患者中观察到纯合变异的患病率更高（4.1%比 0.1%，P = 2×10-7），次要 HCM 基因 MYL2、MYL3 和 CSRP3 的变异更可能呈纯合状态，而主要基因的变异则较少呈纯合状态，这表明这些变异在杂合状态下的外显率较低。隐性 HCM 基因 TRIM63 的双等位基因变异在 2.1%的患者中（比欧洲患者高五倍）被检测到，这突出了隐性遗传在近亲结婚人群中的重要性。最后，与欧洲人相比（40.8%比 61.6%，P = 1.6×10-5），埃及 HCM 患者的罕见变异更不可能被归类为（可能）致病性变异，这是由于当前参考资源中中东人群的代表性不足。在纳入此处提出的利用新的具有匹配祖源的对照的方法后，这一比例增加到 53.3%。
研究近亲结婚人群揭示了与基因检测和我们对 HCM 遗传结构的理解相关的新见解。
